Foamy Cells
Posted March 13, 2010
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Overview
Certain compounds trigger phospholipids to accumulate in the cellular compartments known as lysosomes. Preclinical studies, either in vitro or in laboratory animals, cannot fully predict whether a drug candidate will cause phospholipidosis in humans, in part because of the difficulty of assessing phospholipid accumulation in internal organs of humans without using invasive techniques. Nor is the relationship between phospholipidosis and toxicity clear.
Four experts on drug-induced phospholipidosis met to present the latest information on how pharmaceutical scientists can approach this subject: Mark Reasor of West Virginia University presented an overview of phospholipidosis. David Monteith of Eli Lilly and Company described a tiered screening approach to optimize compounds so that they are less likely to cause phospholipidosis. Steven Vonderfecht of Amgen presented a case scenario of how a pharmaceutical company dealt with the finding that two of its lead candidates caused phospholipidosis. And Lawrence Sancilio of the FDA detailed the agency's efforts to reveal the phospholipidosis-toxicity relationship through the creation of a comprehensive database.
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Web Sites
FDA Critical Path Initiative
The Critical Path Initiative is the FDA's effort to modernize the scientific process through which potential human drugs and devices are transformed from a "proof of concept" into a medical product. Its goals include creating new tools to evaluate drug candidates early in the process to eliminate ones that are unlikely to succeed and focus on those that hold promise.
Pharmaceutical Research and Manufacturers of America (PhRMA)
An organization that represents the leading U. S. pharmaceutical research and biotechnology companies, and advocates for public policies that encourage discovery of new medicines.
Society of Toxicology
The Society is a professional and scholarly organization of scientists from academic institutions, government, and industry representing the scientists who practice toxicology in the U.S. and abroad.
Journal Articles
Drug-Induced Phospholipidosis: Characteristics and Consequences
Franken, G., H. Lullmann & A. Siegfriedt. 1970. The occurrence of huge cells in pulmonary alveoli of rats treated by an anorexic drug. Arzneimittelforschung. 20: 417.
Kacew, S., M. J. Reasor & Z. Ruben. 1997. Cationic lipophilic drugs: mechanisms of action, potential consequences, and reversibility. Drug Metab. Rev. 29: 355-368.
Lullmann, H., R. Lullmann-Rauch & O. Wassermann. 1973. Drug-induced phospholipidosis. Ger. Med. 3: 128-135.
McCloud, C. M., T. L. Beard, S. Kacew & M. J. Reasor. 1995. In vivo and in vitro reversibility of chlorphentermine-induced phospholipidosis in rat alveolar macrophages. Exp. Mol. Pathol. 62: 12-21.
Reasor, M. J. 1981. Drug-induced lipidosis and the alveolar macrophage. Toxicology 20: 1-33.
Reasor, M. J. 1989. A review of the biology and toxicologic implications of the induction of lysosomal lamellar bodies by drugs. Toxicol. Appl. Pharmacol. 97: 47-56.
Reasor, M. J. & S. Kacew. 1991. Amiodarone pulmonary toxicity: morphologic and biochemical features. Proc. Soc. Exp. Biol. Med. 196: 1-7.
Reasor, M. J. & S. Kacew. 1996. An evaluation of possible mechanisms underlying amiodarone-induced pulmonary toxicity. Proc. Soc. Exp. Biol. Med. 212: 297-304.
Reasor, M. J. & S. Kacew. 2001. Drug-induced phospholipidosis: are there functional consequences? Exp. Biol. Med. (Maywood) 226: 825-830. Full Text
Screening for Drug-Induced Phospholipidosis: In Vitro Surrogates and Biomarkers
Casartelli, A. M. Bonato, P. Cristofori, et al. 2003. A cell-based approach for the early assessment of the phospholipidogenic potential in pharmaceutical research and drug development. Cell. Biol. Toxicol. 19: 161-176.
Gonzalez-Rothi, R. J., D. S. Zander & P. R. Ros. 1995. Fluoxetine hydrochloride (Prozac)-induced pulmonary disease. Chest 107: 1763-1765. Full Text
Halstead, B. W., C. M. Zwickl, R. E. Morgan, et al. 2006. A clinical flow cytometric biomarker strategy: validation of peripheral leukocyte phospholipidosis using Nile red. J. Appl. Toxicol. 26: 169-177.
Mortuza, G. B., W. A. Neville, J. Delaney, et al. 2003. Characterisation of a potential biomarker of phospholipidosis from amiodarone-treated rats. Biochim. Biophys. Acta 1631: 136-146.
Ploemen, J. P., J. Kelder, T. Hafmans, et al. 2004. Use of physicochemical calculation of pKa and CLogP to predict phospholipidosis-inducing potential: a case study with structurally related piperazines. Exp. Toxicol. Pathol. 55: 347-355.
Sawada, H., K. Takami & S. Asahi. 2005. A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol. Sci. 83: 282-292. Full Text
Valko, K., C. M. Du, C. D. Beval, et al. 2000. Rapid-gradient HPLC method for measuring drug interactions with immobilized artificial membrane: comparison with other lipophilicity measures. J. Pharm. Sci. 89: 1085-1096.
Phospholipidosis in Drug Development: Management of the Issue in Two Drug Development Programs
Rudmann, D. G., M. E. McNerney, S. L. VanderEide, et al. 2004. Epididymal and systemic phospholipidosis in rats and dogs treated with the dopamine D3 selective antagonist PNU-177864. Toxicol. Pathol. 32: 326-332.
Vonderfecht, S. L., M. L. Stone, R. R. Eversole, et al. 2004. Myopathy related to administration of a cationic amphiphilic drug and the use of multidose drug distribution analysis to predict its occurrence. Toxicol. Pathol. 32: 318-325. Full Text
The FDA Phospholipidosis Working Group
DeGeorge, J. J., C. H. Ahn, P. A. Andrews, et al. 1997. Considerations for toxicology studies of respiratory drug products. Regul. Toxicol. Pharmacol. 25: 189-193.
Lesko, L. J., R. A. Salerno, B. B. Spear, et al. 2003. Pharmacogenetics and pharmacogenomics in drug development and regulatory decision-making: report of the first FDA-PWG-PhRMA-DruSafe workshop. J. Clin. Pharmacol. 43: 342-358.
Additional Articles
Delaney, J., W. A. Neville, A. Swain, et al. 2004. Phenylacetylglycine, a putative biomarker of phospholipidosis: its origins and relevance to phospholipid accumulation using amiodarone treated rats as a model. Biomarkers 9: 271-290.
Kasahara, T., K. Tomita, H. Murano, et al. 2006. Establishment of an in vitro high-throughput screening assay for detecting phospholipidosis-inducing potential. Toxicol. Sci. 90: 133-141.
Masuda, T., H. Ueyama, K. Nakamura, et al. 2005. Skeletal muscle expression of clathrin and mannose 6-phosphate receptor in experimental chloroquine-induced myopathy. Muscle Nerve 31: 495-502.
Pauluhn, J. 2005. Inhaled cationic amphiphilic drug-induced pulmonary phospholipidosis in rats and dogs: time-course and dose-response of biomarkers of exposure and effect. Toxicology 207: 59-72.
Piccotti, J. R., M. S. LaGattuta, S. A. Knight, et al. 2005. Induction of apoptosis by cationic amphiphilic drugs amiodarone and imipramine. Drug Chem. Toxicol. 28: 117-133.
Rabkin, S. W. 2006. Effect of amiodarone on phospholipid content and composition in heart, lung, kidney and skeletal muscle: Relationship to alteration of thyroid function. Pharmacology 76: 129-135.
Robison, R. L., G. E. Visscher, S. A. Roberts, et al. 1985. Generalized phospholipidosis induced by an amphiphilic cationic psychotropic drug. Toxicol. Pathol. 13: 335-348.
Speakers
Mark J. Reasor, PhD
West Virginia University
e-mail | web site | publications
Mark Reasor is professor of toxicology at West Virginia University. His research focuses on the toxicological effects of chemicals on the lungs of animals. Studies are directed at characterizing the responses of the lungs to drugs and toxic particles while investigating the mechanisms by which the responses occur. Reasor is particularly interested in the toxicities of cationic, amphilphilic drugs, and silica particles. He also works on developing treatments for these disorders.
Reasor received his PhD from Johns Hopkins University and completed his postdoctoral training at the National Institute of Environmental Health Sciences.
David Monteith, PhD
Eli Lilly and Company
e-mail | web site | publications
David Monteith is a research scientist at Lilly Research Laboratories. He received his PhD from the University of Texas School of Public Health at Houston. He is a Diplomate of the American Board of Toxicology and manager of toxicology and ADME for Chorus, a division of Eli Lilly and Company. Formerly, he directed the cellular toxicology laboratories at Lilly Research Laboratories and Parke-Davis and worked to develop surrogate assays for screening and mechanistic investigation of pharmaceutical compounds. Monteith has worked for over 15 years in pharmaceutical research and development.
Steven L. Vonderfecht, PhD
Amgen
e-mail | web site | publications
Steve Vonderfecht is a research veterinary pathologist at Amgen Inc. in Thousand Oaks, CA. He received his DVM from Oklahoma State University and PhD in comparative pathology from the University of California, Davis. He is a diplomate of the American College of Veterinary Pathologists and is currently a senior principal pathologist at Amgen. Formerly, he worked at Eli Lilly Research Laboratories, Pharmacia Corporation, and Merck Research Laboratories and was a faculty member at The Johns Hopkins University School of Medicine. Vonderfecht has worked for nearly 17 years in pharmaceutical research and development.
Lawrence Sancilio, PhD
U.S. Food and Drug Administration
e-mail | publications
Lawrence F. Sancilio was born in Brooklyn, New York. He received his Pharmacy Degree (cum laude) from St. Johns University and his PhD in Pharmacology from Georgetown University. He worked in the drug discovery area at Miles Laboratories and the A.H. Robins Co, where he rose to be director of pharmacology. Sancilio did research in the central nervous system, inflammatory, analgesic, immediate hypersensitivity and gastrointestinal areas. He is a member of the American Society of Pharmacology and Experimental Therapeutics, the Society for Experimental Biology and Medicine, and the Inflammatory and Pulmonary Research Associations. He has been a member of the Pulmonary Division at FDA since 1990.
Catherine Zandonella
Catherine Zandonella is a science writer based in New York City, covering such topics as environmental science, public health, and applied technology. She has a master's degree in public health from the University of California, Berkeley. Zandonella has written for a number of publications, including New Scientist, The Scientist, and Nature.